Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

作者：Ditte Demontis, Raymond Kenney Walters, Joanna Martin, Manuel Mattheisen, Thomas D. Als, Esben Agerbo, Gísli Baldursson, Rich Belliveau, Jonas Bybjerg‐Grauholm, Marie Bækvad‐Hansen, Felecia E. Cerrato, Kimberly Chambert, Claire Churchhouse, Ashley Dumont, Nicholas Eriksson, Michael J. Gandal, Jacqueline I. Goldstein, Katrina L. Grasby, Jakob Grove, Ólafur Ó. Guðmundsson, Christine Søholm Hansen, Mads E. Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Nicholas G. Martin, Jennifer L. Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise Robinson, F. Kyle Satterstrom, Hreinn Stefánsson, Christine R. Stevens, Patrick K. Turley, G. Bragi Walters, Hyejung Won, Margaret J. Wright, Ole A. Andreassen, Philip J. Asherson, Christie L. Burton, Dorret Irene Boomsma, Bru Cormand, Søren Dalsgaard, Barbara Franke, Joel E. Gelernter, Daniel H. Geschwind, Hakon H. Hakonarson, Jan Haavik, Henry R. Kranzler, Jonna Kuntsi, K. Langley, Klaus‐Peter Lesch, Christel Maria Middeldorp, Andreas Reif, Luís Augusto Rohde, Panos Roussos, Russell James Schachar, Pamela B. Sklar, Edmund J. S. Sonuga-Barke, Patrick F. Sullivan, Anita Thapar, Joyce Y. Tung, Irwin D. Waldman, Sarah Elizabeth Medland, Kāri Stefánsson, Merete Nordentoft, DAVID MICHAEL HOUGAARD, Thomas Mears Werge, Ole N Mors, Preben Bo Mortensen, Mark J. Daly, Stephen V. Faraone, Anders Dupont Børglum, Benjamin M. Neale · 发表于：Nature Genetics · 年份：2018 · DOI：10.1038/s41588-018-0269-7 · 被引用次数：2356 · 研究领域：Attention Deficit Hyperactivity Disorder、Genetics and Neurodevelopmental Disorders、Genetic Associations and Epidemiology

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.